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Pseudogene bnip3P1 Regulates H. pylori–Induced Apoptosis in Gastric Mucosal by Acting on the miR-411-5p/bnip3 Axis

Cellular Microbiology 2025年第1期2025卷

作者： Zhang, Andong Yan, Xin Li, Ningzhe Yan, Shiying Li, Shu Yang, Hua Liu, Yimeng Zhang, Jian Wang, Jia Zhao, Jian Cao, Mei Sichuan University Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education Sichuan University Chengdu China Sichuan Academy of Medical Sciences and Sichuan People’s Hospital University of Electronic Science and Technology of China Chengdu China

Helicobacter pylori (H. pylori) is one of the major causes of gastric mucosal damage, and infection with H. pylori induces an immune response with gastric mucosal cells, which reduces gastric mucosal damage. The pseudogene bnip3P1, sharing a remarkable 95.92% similarity with its well-characterized counterpart bnip3, has largely remained unexplored. To elucidate the role of bnip3P1 in gastric mucosal damage induced by H. pylori infection, we meticulously constructed both in vivo and in vitro models. Gene chip sequencing, dual-luciferase assays, and cellular phenotyping were detected. We uncovered a compelling positive correlation between the duration of H. pylori infection and bnip3 overexpression at both the mRNA and protein levels. Intriguingly, overexpression of bnip3 was found to effectively impede the proliferation and migration of human gastric epithelial cells (GES-1). Furthermore, we identified miR-411-5p as a direct regulator of bnip3, targeting its 3 ^′UTR region and suppressing its expression during H. pylori infection. Notably, bnip3P1- 3^′UTR was observed to competitively bind miR-411-5p, leading to the upregulation of bnip3 expression. Furthermore, overexpression of bnip3P1 was associated with a marked decrease in GES-1 cell proliferation and a concomitant acceleration of apoptosis. Our findings suggest that bnip3P1 functions as a competing endogenous RNA (ceRNA) within the bnip3/miR-411-5p axis during H. pylori infection, which ultimately hinders cell proliferation and promotes apoptosis in GES-1 cells. This study sheds light on the intricate mechanisms underlying H. pylori infection of GES-1 cells. Copyright © 2025 Andong Zhang et al. Cellular Microbiology published by John Wiley & Sons Ltd.

关键词： apoptosis bnip3 bnip3P1 Helicobacter pylori miR-411-5p proliferation

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bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak

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BIOCHEMICAL JOURNAL 2007年第Pt 3期405卷 407-415页

作者： Kubl, Dieter A. Ycaza, John E. Gustafsson, Asa B. Scripps Res Inst Dept Mol & Expt Med La Jolla CA 92037 USA

bnip3 is a pro-apoptotic member of the Bcl-2 family that is down-regulated in pancreatic cancers, which correlates with resistance to chemotherapy and a worsened prognosis. In contrast, bnip3 is up-regulated in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion). bnip3 exerts its action at the mitochondria, but the mechanism by which bnip3 mediates mitochondrial dysfunction is not clear. In the present study, we have identified Bax and Bak as downstream effectors of bnip3-mediated mitochondrial dysfunction. bnip3 plays a role in hypoxia-mediated cell death, but MEFs (mouse embryonic fibroblasts) derived from mice deficient in Bax and Bak were completely resistant to hypoxia even with substantial up-regulation of bnip3. These cells were also resistant to bnip3 overexpression, but re-expression of Bax or Bak restored susceptibility to bnip3, suggesting that bnip3 can act via either Bax or Bak. In contrast, bnip3 overexpression in wild-type MEFs induced mitochondrial dysfunction with loss of membrane potential and release of cytochrome c. Cell death by bnip3 was reduced in the presence of mPTP (mitochondrial permeability transition pore) inhibitors, but did not prevent bnip3-mediated activation of Bax or Bak. Moreover, overexpression of bnip3 Delta TM, a dominant-negative form of bnip3, reduced translocation of GFP (green fluorescent protein)-Bax to mitochondria during sI/R (simulated I/R) in HL-1 myocytes. Similarly, down-regulation of bnip3 using RNA interference decreased activation of Bax in response to sI/R in HL-1 myocytes. These results suggest that bnip3 mediates mitochondrial dysfunction through activation of Bax or Bak which is independent of mPTP opening.

关键词： apoptosis Bak Bax bnip3 ischaemia/reperfusion mitochondrial permeability transition pore

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bnip3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF

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ONCOGENE 2003年第30期22卷 4734-4744页

作者： Kothari, S Cizeau, J McMillan-Ward, E Israels, SJ Bailes, M Ens, K Kirshenbaum, LA Gibson, SB Univ Manitoba Manitoba Inst Cell Biol Winnipeg MB Canada St Boniface Gen Hosp Res Ctr Inst Cardiovasc Sci Winnipeg MB R2H 2A6 Canada Univ Manitoba Fac Med Dept Physiol Winnipeg MB Canada Univ Manitoba Fac Med Dept Biochem & Med Genet Winnipeg MB Canada

Hypoxic regions within solid tumors are often resistant to chemotherapy and radiation. bnip3 (Bcl-2/E1B 19 kDa interacting protein) is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. During hypoxia, bnip3 expression is increased in many cell types and upon forced overexpression bnip3 induces cell death. Herein, we have demonstrated that blockage of hypoxia-induced bnip3 expression using antisense oligonucleotides against bnip3 or blockage of bnip3 function through expression of a mutant form of bnip3 inhibits hypoxia-induced cell death in human embryonic kidney 293 cells. We have also determined that hypoxia-mediated bnip3 expression is regulated by the transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha) in human epithelial cell lines. Furthermore, HIF-1alpha directly binds to a consensus HIF-1alpha-responsive element (HRE) in the human bnip3 promoter that upon mutation of this HRE site eliminates the hypoxic responsiveness of the promoter. Since bnip3 is expressed in hypoxic regions of tumors but fails to induce cell death, we determined whether growth factors block bnip3-induced cell death. Treatment of the breast cancer cell line MCF-7 cells with epidermal growth factor (EGF) or insulin-like growth factor effectively protected these cells from bnip3-induced cell death. Furthermore, inhibiting EGF receptor signaling using antibodies against ErbB2 (Herceptin) resulted in increased hypoxia-induced cell death in MCF-7 cells. Taken together, bnip3 plays a role in hypoxia-induced cell death in human epithelial cells that could be circumvented by growth factor signaling.

关键词： hypoxia cell death tumor bnip3 EGF IGF

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The carboxy terminal c-tail of bnip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondrial

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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2002年第2期398卷 147-152页

作者： Kim, JY Cho, JJ Ha, J Park, JH Kyung Hee Univ Coll Med Dept Pathol Seoul 130701 South Korea Kyung Hee Univ Coll Med Dept Microbiol Seoul 130701 South Korea Kyung Hee Univ Coll Med Dept Mol Biol Seoul 130701 South Korea

bnip3 is a member of Bcl-2 family proteins that displays proapoptotic activity. It contains Bcl-2 homology (1311) 3 and single carboxy terminal membrane-anchoring domain (TM), which targets to specific intracellular organelles, especially to mitochondria. Mitochondria play significant roles in apoptosis by releasing apopto-genic factors through large conductance channel known as permeability transition pore (PTP). Although bnip3 associates with mitochondria when overexpressed, apoptotic pathways including mitochondrial cascade and functional domains of bnip3 are still unknown. in this report, we demonstrate that recombinant bnip3 (rbnip3) induces mitochondrial permeability transition (MPT) and cytochrome c release from isolated mitochondria, which are inhibited by the PT inhibitor cyclosporin A (CsA). We further show that carboxy terminal tail of bnip3, but not BH3, is essential for the induction of PT and cytochrome c release on the base of mutational analysis. Moreover, addition of carboxy terminal c-tail to TM substitution mutant, which did not induce the PT and cytochrome c release, restored PT-inducing activity. Taken together, our results suggest that bnip3 exerts proapoptotic activity through PT induction and that carboxy terminal c-tail is crucial for it. (C) 2002 Elsevier Science (USA).

关键词： bnip3 permeability transition BH3 transmembrane domain cytochrome c

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bnip3-mediated mitochondrial autophagy is independent of the mitochondrial permeability transition pore

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AUTOPHAGY 2010年第7期6卷 855-862页

作者： Quinsay, Melissa N. Thomas, Robert L. Lee, Youngil Gustafsson, Asa B. Univ Calif San Diego Skaggs Sch Pharm & Pharmaceut Sci La Jolla CA 92093 USA

bnip3 is a pro-apoptotic BH3-only protein which is associated with mitochondrial dysfunction and cell death. bnip3 is also a potent inducer of autophagy in many cells. In this study, we have investigated the mechanism by which bnip3 induces autophagy in adult cardiac myocytes. Overexpression of bnip3 induced extensive autophagy in adult cardiac myocytes. Fluorescent microscopy studies and ultrastructural analysis revealed selective degradation of mitochondria by autophagy in myocytes overexpressing bnip3. Oxidative stress and increased levels of intracellular Ca2+ have been reported by others to induce autophagy, but bnip3-induced autophagy was not abolished by antioxidant treatment or the Ca2+ chelator BAPTA-AM. We also investigated the role of the mitochondrial permeability transition pore (nnPTP) in bnip3-induced autophagy. Although the mPTP has previously been implicated in the induction of autophagy and selective removal of damaged mitochondria by autophagosonnes, mitochondria sequestered by autophagosomes in bnip3-treated cardiac myocytes had not undergone permeability transition and treatment with the mPTP inhibitor cyclosporine A did not inhibit mitochondrial autophagy in cardiac myocytes. Moreover, cyclophilin D (cypD) is an essential component of the mPTP and bnip3 induced autophagy to the same extent in embryonic fibroblasts isolated from wild-type and cypD-deficient mice. These results support a model where bnip3 induces selective removal of the mitochondria in cardiac myocytes and that bnip3 triggers induction of autophagy independent of Ca2+, ROS generation and nnPTP opening.

关键词： bnip3 autophagy cardiac myocytes mitochondria permeability transition pore cyclophilin D

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bnip3-mediated autophagy via the mTOR/ULK1 pathway induces primordial follicle loss after ovarian tissue transplantation

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JOURNAL OF ASSISTED REPRODUCTION AND GENETICS 2023年第3期40卷 491-508页

作者： Liu, Fengxia Li, Mujun Guangxi Med Univ Nanning 530021 Peoples R China Guangxi Med Univ Affiliated Hosp 1 Dept Reprod Med Res Ctr Nanning 530021 Peoples R China

PurposeTo explore the underlying mechanism of primordial follicle loss in the early period following ovarian tissue transplantation (OTT).Methodsbnip3 was selected through bioinformatic protocols, as the hub gene related to autophagy during OTT. bnip3 and autophagy in mice ovarian grafts and in hypoxia-mimicking KGN cells were detected using immunohistochemistry, transmission electron microscopy (TEM), western blotting, qPCR, and fluorescence staining. The regulatory role played by bnip3 overexpression and the silencing of KGN cells in autophagy via the mTOR/ULK1 pathway was *** examination showed that autophagic vacuoles increased after mice ovarian auto-transplantation. The bnip3 and autophagy-related proteins (Beclin-1, LC3B, and SQSTM1/p62) in mice ovarian granulosa cells of primordial follicle from ovarian grafts were altered compared with the control. Administration of an autophagy inhibitor in mice decreased the depletion of primordial follicles. In vitro experiments indicated that bnip3 and autophagy activity were upregulated in KGN cells treated with cobalt chloride (CoCl2). The overexpression of bnip3 activated autophagy, whereas the silencing of bnip3 suppressed it and reversed the autophagy induced by CoCl2 in KGN cells. Western blotting analysis showed the inhibition of mTOR and activation of ULK1 in KGN cells treated with CoCl2 and in the overexpression of bnip3, and the opposite results following bnip3 silencing. The activation of mTOR reversed the autophagy induced by bnip3 ***3-induced autophagy is crucial in primordial follicle loss during OTT procedure, and bnip3 is a potential therapeutic target for primordial follicle loss after OTT.

关键词： Ovarian tissue transplantation bnip3 Autophagy mTOR ULK1 pathway

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Upregulation of bnip3 mediated by ERK/HIF-1α pathway induces autophagy and contributes to anoikis resistance of hepatocellular carcinoma cells

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FUTURE ONCOLOGY 2014年第8期10卷 1387-1398页

作者： Sun, Lei Li, Tao Wei, Qing Zhang, Ying Jia, Xiaoqing Wan, Zhengkun Han, Lihui Shandong Univ Sch Med Dept Immunol Jinan 250012 Peoples R China Shandong Univ Prov Hosp Dept Infect Dis Jinan 250021 Peoples R China Shandong Univ Qilu Hosp Dept Gastroenterol Jinan 250012 Peoples R China

Aim: Acquisition of anoikis resistance is the hallmark of cancer and has been shown to be involved in metastasis of melignant cells. Our previous work showed that anoikis resistance is associated with the metastasis of hepatocellular carcinoma (HCC) cells. The aim of this study is to elucidate the mechanisms of this course. Materials & methods: Expression of bnip3 and HIF-1 alpha at the mRNA and protein level in HCC cells were detected by realtime PCR and western blot, respectively. Autophagy activation and signaling transduction pathway were detected by western blot. Cell viabilities were detected by CCK8 assay and trypan blue exclusion assay. Results: Upregulation of bnip3 promoted the activation of autophagy, one type of cell survival strategy in response to external stress, by suppressing mTOR/S6K1 signaling system. The upregulation of bnip3 was mediated by ERK/HIF-1 alpha pathway, which further contributed to anoikis resistance of HCC cells through the mTORC1 signaling pathway. Conclusion: Upregulation of bnip3 contributs to anoikis resistance of HCC cells, and bnip3 may serve as a novel therapeutic target for manipulation of cancer metastasis.

关键词： anoikis resistance autophagy bnip3 hepatocellular carcinoma mTOR/S6K1

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bnip3 contributes to cisplatin-induced apoptosis in ovarian cancer cells

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FEBS OPEN BIO 2020年第8期10卷 1463-1473页

作者： Jia, Jinghui Yang, Xiaoxin Zhao, Qing Ying, Feiquan Cai, E. Sun, Si He, Xiaoqi Air Force Gen Hosp Dept Obstet & Gynecol PLA Beijing Peoples R China Huazhong Univ Sci & Technol Union Hosp Tongji Med Coll Dept Obstet & Gynecol Wuhan 430022 Peoples R China WuHan Univ Wuhan Hosp 3 Tongren Hosp Dept Obstet & Gynecol Wuhan Peoples R China Huazhong Univ Sci & Technol Cent Hosp Wuhan Tongji Med Coll Dept Obstet & Gynecol Wuhan Peoples R China

bnip3 is a proapoptotic protein that mediates apoptosis, necrosis and autophagy. However, the involvement of bnip3 in cisplatin-induced apoptosis in ovarian cancer is not clear. In this study, we examined the role of bnip3 in ovarian cancer during cisplatin treatment and its correlation with clinical outcomes. We first measured cisplatin cytotoxicity and bnip3 levels before and after cisplatin exposure for ovarian cancer cell lines A2780, SKOV3, OVCAR4, OV2008, ES2 and HO8910. bnip3 was observed to be differentially expressed in these cell lines, and cisplatin induced a significant increase in bnip3 levels in A2780 and OVCAR4. bnip3 knockdown with siRNA in A2780 and OVCAR4 significantly reduced cisplatin cytotoxicity in these two cell lines and alleviated cisplatin-induced apoptosis. We searched the online databases Gene Expression Omnibus and The Cancer Genome Atlas to analyze the correlation between bnip3 level and overall survival and progression-free survival in patients with ovarian cancer. Pooled analyses showed that higher bnip3 level was correlated with poorer overall survival (95% confidence intervals;hazard ratio = 1.18, 1.04-1.34;P = 0.013) and progression-free survival (95% confidence intervals;hazard ratio = 1.26, 1.10-1.43;P = 0.00049). However, the results of individual datasets and stratification analyses of histology, FIGO (Federation Internationale de Gynecolgie et d'Obstetrique) stage, chemotherapy regimen and P53 mutation status varied. These findings indicate that cisplatin-induced apoptosis is dependent on bnip3 level in ovarian cancer cell lines. Targeting bnip3 may therefore be a potential way of restoring cisplatin sensitivity.

关键词： apoptosis bnip3 cisplatin cisplatin sensitization ovarian cancer

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bnip3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

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DIABETOLOGIA 2016年第3期59卷 571-581页

作者： Choi, Jin Woo Jo, Anna Kim, Min Park, Ho Seon Chung, Sung Soo Kang, Shinae Park, Kyong Soo Seoul Natl Univ Coll Med Dept Internal Med 101 Daehak Ro Seoul 03080 South Korea Seoul Natl Univ Coll Med Dept Biomed Sci Seoul 03080 South Korea Seoul Natl Univ Grad Sch Convergence Sci & Technol Dept Mol Med & Biopharmaceut Sci Seoul 03080 South Korea Yonsei Univ Coll Med Gangnam Severance Hosp Dept Internal Med 211 Eonju Ro 146-92 Dogok Dong Seoul 135710 South Korea Yonsei Univ Coll Med Severance Inst Vasc & Metab Res Seoul 135710 South Korea

Aims/hypothesis Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (bnip3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of bnip3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-gamma (PPAR gamma)-induced adipose tissue remodelling. Methods The expression of bnip3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in bnip3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). Results The protein bnip3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, bnip3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, bnip3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of bnip3 was restored by rosiglitazone treatment. Knockdown of bnip3 in adipocytes inhibited rosiglitazoneinduced mitochondrial biogenesis and function, partially mediated by the 5' AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma, co-activator 1 alpha (PGC1 alpha) signalling pathway. Rosiglitazone treatment increased the transcription level of bnip3 in the reporter assay and the presence of the PPRE site in the bnip3 promoter was demonstrated by EMSA. Conclusions/interpretation The protein bnip3 contributes to the improvement of mitochondrial bioenergetics that occurs on exposure to rosiglitazone. It may be a novel therapeutic target for restoring mitochondrial dysfunction under insulin-resistant conditions.

关键词： Adipocytes Bioenergetics bnip3 Insulin resistance Mitochondria PPRE Rosiglitazone

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bnip3 and signal-specific programmed death in the heart

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JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 2005年第1期38卷 35-45页

作者： Webster, KA Graham, RM Bishopric, NH Univ Miami Med Ctr Dept Mol & Cellular Pharmacol Miami FL 33136 USA Univ Miami Med Ctr Vasc Biol Inst Miami FL 33101 USA Univ Miami Med Ctr Dept Med Miami FL 33136 USA Univ Miami Med Ctr Dept Pediat Miami FL 33136 USA

The BH3-only proteins, including bnip3, are members of the Bcl-2 family of cell death-regulating factors. Whereas proteins such as Bax and Bak play a central role in most forms of apoptosis, the BH3-only proteins appear to modulate apoptosis through cell type- and signal-specific pathways. This review will focus oil our studies of the specific role of bnip3 in cardiac myocyte apoptotic signaling during ischemia. We recently showed that hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the [pH](o) drops below 6.5. A micro-array analysis of 20,000 genes identified the pro-apoptotic Bcl-2 family member bnip3 as one of the most strongly upregulated of >100hypoxia-inducible genes in cardiac myocytes. bnip3 mRNA increased by 12-fold. and bnip3 protein by sixfold. during 24 h of hypoxia-bnip3 protein accumulation was further enhanced by acidosis. bnip3 was loosely bound to mitochondria under conditions of neutral hypoxia but became more tightly associated at acid pH, coincident with opening of the mitochondrial permeability transition pore (MPTP). Subsequent DNA fragmentation and cell death were not blocked by caspase inhibitors, but were inhibited by antisense bnip3 oligonucleotides and MPTP inhibitors, indicating that bnip3 activates ail atypical programmed death pathway with features of both apoptosis and necrosis. The sequential induction and activation of bnip3 by hypoxia and acidosis provide a molecular basis for the observation that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes. (C) 2004 Elsevier Ltd. All rights reserved.

关键词： cardiac myocyte heart apoptosis ischemia pH bnip3 mitochondria necrosi

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